Method and device for three-stage atrial cardioversion therapy

ABSTRACT

Methods and apparatus for a three-stage atrial cardioversion therapy that treats atrial arrhythmias within pain tolerance thresholds of a patient. An implantable therapy generator adapted to generate and selectively deliver a three-stage atrial cardioversion therapy and at least two leads, each having at least one electrode adapted to be positioned proximate the atrium of the patient. The device is programmed for delivering a three-stage atrial cardioversion therapy via both a far-field configuration and a near-field configuration of the electrodes upon detection of an atrial arrhythmia. The three-stage atrial cardioversion therapy includes a first stage for unpinning of one or more singularities associated with an atrial arrhythmia, a second stage for anti-repinning of the one or more singularities, both of which are delivered via the far-field configuration of the electrodes, and a third stage for extinguishing of the one or more singularities delivered via the near-field configuration of the electrodes.

RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 14/257,620, is now U.S. Pat. No. 9,289,620, filed Apr. 21,2014, which is a continuation of U.S. patent application Ser. No.13/349,517, is now U.S. Pat. No. 8,706,216, filed Jan. 12, 2012, whichis a continuation-in-part of U.S. patent application Ser. No.12/776,196, filed May 7, 2010, now issued as U.S. Pat. No. 8,560,066,which is a continuation-in-part of U.S. patent application Ser. No.12/333,257, filed Dec. 11, 2008, now issued as U.S. Pat. No. 8,509,889,which claims the benefit of U.S. Provisional Application No. 61/012,861,filed Dec. 11, 2007, the disclosures of which are incorporated herein byreference.

GOVERNMENT INTEREST

This invention was made with government support under Contract NumberHL067322 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

FIELD OF THE INVENTION

The present disclosure relates generally to the treatment of atrialarrhythmias, such as atrial fibrillation (“AF”) and atrial flutter(“AFl”). More particularly, the present disclosure relates to devicesand methods of using low-energy electrical stimuli from an implantabledevice that delivers a three-stage atrial cardioversion therapy todestabilize and extinguish reentry mechanisms that maintain AF and AFl.

BACKGROUND OF THE INVENTION

Atrial tachyarrhythmias are the most common atrial arrhythmia, presentlyestimated to affect approximately 2.3 million Americans. There are twoprimary forms of atrial tachyarrhythmias, AF and AFl, with relativeoccurrence in their chronic forms of about 10:1, respectively. Currentprojections suggest that by the year 2050, between about twelve andabout fifteen million Americans will suffer from AF. The enormity of theproblem is magnified by its well-described clinical consequences:thromboembolic stroke, congestive heart failure (“CHF”), cognitivedysfunction, and possibly increased mortality.

Many different factors can promote the initiation and maintenance of AFand AFl. Several cardiac disorders can predispose patients to AF,including coronary artery disease, pericarditis, mitral valve disease,congenital heart disease, CHF, thyrotoxic heart disease, andhypertension. Many of these are thought to promote AF by increasingatrial pressure and/or causing atrial dilation. AF also occurs inindividuals without any evidence of heart or systemic disease, acondition known as “lone AF,” which primarily involves the autonomicnervous system.

Both AF and AFl are maintained by a reentry mechanism. Specifically,atrial tissue continually excites itself, creating reentrant, i.e.circular or tornado-like patterns of excitation. AFl is generallydefined as a macro-reentrant circuit, which can rotate around afunctional or anatomic line of block. Major anatomical structures areusually involved in defining one or several simultaneous reentrycircuit(s), including the region between superior and inferior venaecavae in the right atrium, and the pulmonary vein region in the leftatrium. If the cycle length (“CL”) of the reentry remains relativelylong, one-to-one conduction can remain throughout the entire atria andAFl can be observed. However, if the CLs of reentry circuits aresufficiently short, waves of excitation produced by the reentrantcircuit break up in the surrounding atrial tissue and AF can ensue. Themorphology of electrograms during AFl or AF depends on the anatomiclocation and frequency of reentrant circuits that cause the arrhythmia.

There are clear interactions between AF and AFl. AFl is defined as thepresence of a single, constant, and stable reentrant circuit. AF, on theother hand, can be due to random activation in which multiple reentrantwavelets of the leading circle type (mother rotor) continuouslycirculate in directions determined by local excitability,refractoriness, and anatomical structure. AF can be converted to AFl,and vice versa, spontaneously or as a result of an intervention, such asdrug administration, DC cardioversion, or atrial pacing.

AF is the most prevalent clinical arrhythmia in the world and, with anaging population, has the potential of becoming an increasing cause ofmorbidity and mortality. Although several options for pharmaceuticaltreatment exist, for some patients, particularly those with paroxysmalAF, drug therapy can be ineffective. In addition, anti-arrhythmic drugscan have serious proarrhythmic side effects. Therefore,non-pharmacologic treatments of AF are needed.

One alternative to pharmacological treatment of AF is a cardiac ablationprocedure. While there have been many advances in ablative techniques,these procedures are not without risks. Such risks can include cardiacperforation, esophageal injury, embolism, phrenic nerve injury, andpulmonary vein stenosis. There are also implantable devices currently onthe market for the treatment of atrial tachyarrhythmias. Some of thesedevices apply near-field overdrive pacing, also known as antitachycardiapacing (“ATP”); conventional high-energy far field defibrillationshocks; or a combination thereof. As described, for example in U.S. Pat.No. 5,562,708 to Combs et al., ATP works by delivering a burst of pacingstimuli at an empirically chosen frequency at a single pacing site inorder to stimulate the excitable gap of a reentrant circuit, disruptingand terminating the circuit.

The use of an alternative kind of ATP delivered from far-fieldelectrodes and known as far-field overdrive pacing has been proposed forimplantable devices as described, for example, in U.S. Pat. No.5,265,600 to Adams et al., U.S. Pat. No. 5,676,687 to Ayers, U.S. Pat.No. 6,510,342 to Park et al., U.S. Pat. No. 6,813,516 to Ujhelyi et al.,and U.S. Pat. Nos. 7,079,891, and 7,113,822 to Kroll. U.S. Pat. No.5,676,687 to Ayers and U.S. Pat. No. 6,185,459 to Mehra et al. bothdescribe an overdrive pacing arrangement that is delivered fromnear-field electrodes instead of far-field electrodes. The overdrivepacing arrangement is described in these patents as being used inconjunction with conventional kinds of defibrillation therapy where theoverdrive pacing is utilized to prevent the recurrence of an AF.

Although ATP can be effective for slower AFls, the effectiveness of ATPcan diminish for CLs below about two hundred milliseconds (“ms”) and canbe ineffective for faster AFl and AF. ATP failure can occur when thepacing lead is located at a distance from the reentrant circuit and thepacing-induced wavefront is annihilated before reaching the circuit.This can be a highly probable scenario for faster arrhythmias. Inaddition, the continued application of far-field ATP is known topotentially induce ventricular fibrillation, although the timing of thedelivery of ATP can reduce the potential for inducing ventricularfibrillation and potential recurrence of AF as described, for example,in U.S. Pat. No. 6,091,991 to Warren, U.S. Pat. No. 6,847,842 toRodenhiser et al., U.S. Pat. No. 7,110,811 to Wagner et al., and U.S.Pat. No. 7,120,490 to Chen et al.

Another manner in which atrial arrhythmias have been treated is withstandard external defibrillators with the patient sedated duringdelivery of a defibrillation shock. There have also been externaldefibrillation systems, such as that disclosed in U.S. Pat. No.5,928,270 to Ramsey, specifically designed for use with atrialarrhythmias. However, in order to provide an external shock that caneffectively terminate arrhythmias with electrode placed externally onthe body, such systems must provide higher energy shocks than would berequired by implantable devices. In addition, externally applied shocksnecessarily recruit more of the skeletal musculature resulting inpotentially more pain and discomfort to the patient.

Another method of treatment for patients with recurrent persistent AF isthe implantable atrial defibrillator (“IAD”), such as described in U.S.Pat. No. 3,738,370 to Charms, and U.S. Pat. No. 3,942,536 to Mirowski.Although initial clinical trials have shown that IADs have a highspecificity and sensitivity to AF and deliver safe and effective shocks,the energy level needed for successful cardioversion can exceed the painthreshold. Endocardial cardioversion shock energies greater than 0.1 Jare perceived to be uncomfortable (Ladwig, K. H., Marten-Mittag, B.,Lehmann, G., Gundel, H., Simon, H., Alt, E., Absence of an Impact ofEmotional Distress on the Perception of Intracardiac Shock Discharges,International Journal of Behavioral Medicine, 2003, 10(1): 56-65), andpatients can fail to distinguish energy levels higher than this and findthem equally painful. The pain threshold depends on many factors,including autonomic tone, presence of drugs, location of electrodes andshock waveforms. Moreover, pain thresholds can be different from patientto patient.

Various approaches have sought to lower the energy level required foreffective atrial fibrillation. A number of systems, such as, forexample, U.S. Pat. No. 5,282,836 to Kreyenhagen et al., U.S. Pat. No.5,797,967 to KenKnight, U.S. Pat. Nos. 6,081,746, 6,085,116, and6,292,691 to Pendekanti et al., and U.S. Pat. Nos. 6,556,862 and6,587,720 to Hsu et al. disclose application of atrial pacing pulses inorder to lower the energy level necessary for atrial defibrillationshocks. The energy delivered by pacing pulses is relatively nominal incomparison to defibrillation shocks. U.S. Pat. No. 5,620,468 to Mongeonet al. discloses applying cycles of low energy pulse bursts to theatrium to terminate atrial arrhythmias. U.S. Pat. No. 5,840,079 toWarman et al. discloses applying low-rate ventricular pacing beforedelivering atrial defibrillation pulses. U.S. Pat. Nos. 6,246,906 and6,526,317 to Hsu et al. disclose delivering both atrial and ventricularpacing pulses prior to delivering an atrial defibrillation pulse. U.S.Pat. No. 5,813,999 to Ayers et al. discloses the use of biphasic shocksfor atrial defibrillation. U.S. Pat. Nos. 6,233,483 and 6,763,266 toKroll discloses the use of multi-step defibrillation waveform, whileU.S. Pat. No. 6,327,500 to Cooper et al. discloses delivering tworeduced-energy, sequential defibrillation pulses instead of one largerenergy defibrillation pulse.

Other systems have sought to lower the patient's perception of the painassociated with atrial defibrillation shocks. For example, U.S. Pat. No.5,792,187 to Adams applies electromagnetic stimulation of nervestructures in the area of the shock to block the transmission of thepain signal resulting from the shock. U.S. Pat. No. 6,711,442 toSwerdlow et al. and U.S. Pat. Nos. 7,155,286 and 7,480,351 to Kroll etal. disclose application of a “prepulse” prior to application of a highvoltage shock pulse in order to reduce the perceived pain and startleresponse caused by the shock pulse. U.S. Pat. No. 5,925,066 to Kroll etal. discloses a drug delivery system in combination with anti-tachypacing for inhibiting pain upon detection of atrial fibrillation. U.S.Pat. No. 7,142,927 to Benser measures the physical displacement of anunconscious patient in response to various shock levels and programs anarrhythmia treatment device to provide shocks that will not cause anexcessive level of discomfort.

Despite these efforts, there remains a need for improved atrialarrhythmia treatment methods and devices enabling successful electricaltreatment without exceeding the pain threshold of any given patient andwithout relying on pharmacological or ablative treatments.

Embodiments of methods and apparatus in accordance with the presentdisclosure provide for a three-stage atrial cardioversion therapy totreat atrial arrhythmias within pain tolerance thresholds of a patient.An atrial arrhythmia treatment in accordance with various embodimentsincludes an implantable therapy generator adapted to generate andselectively deliver a three-stage atrial cardioversion therapy and atleast two leads operably connected to the implantable therapy generator,each lead having at least one electrode adapted to be positionedproximate the atrium of a heart of the patient. The atrial arrhythmiatreatment device is programmed with a set of therapy parameters fordelivering a three-stage atrial cardioversion therapy to a patient viaboth a far-field configuration and a near-field configuration of theelectrodes upon detection of an atrial arrhythmia by the atrialarrhythmia treatment device.

The three-stage atrial cardioversion therapy includes a first stage forunpinning of one or more singularities associated with an atrialarrhythmia, a second stage for anti-repinning of the one or moresingularities associated with the atrial arrhythmia, and a third stagefor extinguishing of the one or more singularities associated with theatrial arrhythmia. In various embodiments, the first stage comprises twoto ten far-field atrial cardioversion pulses of more than 10 volts andless than 100 volts. In one such embodiment, the first stage comprisestwo biphasic pulses with a voltage amplitude ranging from 10 volts to 30volts. Pulse duration may be less than 10 milliseconds and a pulsecoupling interval ranges 20 to 50 milliseconds, and the first stage hasa total duration of less than two cycle lengths of the atrial arrhythmiaand is triggered in relation to an R-wave and delivered within aventricular refractory period with an energy of each biphasic atrialcardioversion pulse less than 0.1 joules.

In an embodiment, the second stage comprises five to ten far fieldpulses of ultra-low energy monophasic pulses with a pulse duration ofmore than 5 and less than 20 milliseconds and a pulse coupling intervalof between 70-100% of the cycle length of the atrial arrhythmia. In onesuch embodiment, the second stage comprises six monophasic shocks of onevolt to three volts.

In an embodiment, the third stage comprises five to ten near fieldpulses with a pulse duration of more than 0.2 and less than 5milliseconds and a pulse coupling interval of between 70-100% of thecycle length of the atrial arrhythmia. In one such embodiment, the thirdstage pulses are paced at 88% of the atrial fibrillation cycle lengthand at three times the near-field atrial capture threshold. Thethree-stage atrial cardioversion therapy is delivered in response todetection of the atrial arrhythmia with each stage having an inter-stagedelay of between 50 to 400 milliseconds and in some embodiments, withoutconfirmation of conversion of the atrial arrhythmia until after deliveryof the third stage.

In various embodiments, an atrial arrhythmia treatment apparatusincludes at least one electrode adapted to be implanted proximate anatrium of a heart of a patient to deliver far field pulses and at leastone electrode adapted to implanted proximate the atrium of the heart ofthe patient to deliver near field pulses and sense cardiac signals. Animplantable therapy generator is operably connected to the electrodesand includes a battery system operably coupled and providing power tosensing circuitry, detection circuitry, control circuitry, and therapycircuitry of the implantable therapy generator. The sensing circuitrysenses cardiac signals representative of atrial activity and ventricularactivity. The detection circuitry evaluates the cardiac signalsrepresentative of atrial activity to determine an atrial cycle lengthand detect an atrial arrhythmia based at least in part on the atrialcycle length. The control circuitry, in response to the atrialarrhythmia, controls generation and selective delivery of a three-stageatrial cardioversion therapy to the electrodes with each stage having aninter-stage delay of 500 to 400 and without confirmation of conversionof the atrial arrhythmia during the three-stage atrial cardioversiontherapy. The therapy circuitry is operably connected to the electrodesand the control circuitry and includes at least one first stage chargestorage circuit selectively coupled to the at least one far fieldelectrode that selectively stores energy for a first stage of thethree-stage atrial cardioversion therapy, at least one second stagecharge storage circuit selectively coupled to the at least one far fieldelectrode that selectively stores a second stage of the three-stageatrial cardioversion therapy, and at least one third stage chargestorage circuit selectively coupled to the near field electrode thatselectively stores a third stage of the three-stage cardioversiontherapy.

The methods and devices of the present disclosure can exploit a virtualelectrode polarization (“VEP”) enabling successful treatment of AF andAFl with an implantable system without exceeding the pain threshold ofany given patient. This is enabled by far-field excitation of multipleareas of atrial tissue at once, rather than just one small area near apacing electrode, which can be more effective for both AFl and AF. Themethods can differ from conventional defibrillation therapy, whichtypically uses only one high-energy (about one to about seven joules)monophasic or biphasic shock or two sequential monophasic shocks fromtwo different vectors of far-field electrical stimuli. To account forpain threshold differences in patients, a real-time feedback to thepatient can be provided in estimating the pain threshold during thecalibration and operation of the implantable device.

The methods and devices of embodiments of the present disclosure canutilize a low-voltage phased unpinning far-field therapy together withnear-field therapy that forms the three-stage atrial cardioversiontherapy to destabilize or terminate the core of mother rotor, whichanchors to a myocardial heterogeneity such as the intercaval region orfibrotic areas. A significant reduction in the energy required toconvert an atrial arrhythmia can be obtained with this unpinning,anti-repinning and then extinguishing technique compared withconventional high-energy defibrillation, thus enabling successfulcardioversion without exceeding the pain threshold of a patient.

Applying far-field low energy electric field stimulation in anappropriate range of time- and frequency-domains can interrupt andterminate the reentrant circuit by selectively exciting the excitablegap near the core of reentry. By stimulating the excitable gap near thecore of the circuit, the reentry can be disrupted and terminated. Thereentrant circuit is anchored at a functionally or anatomicallyheterogeneous region, which constitutes the core of reentry. Areas nearthe heterogeneous regions (including the region of the core of reentry)will experience greater polarization in response to an applied electricfield compared with the surrounding, more homogeneous tissue. Thus, theregion near the core of reentry can be preferentially excited with verysmall electric fields to destabilize or terminate anchored reentrantcircuits. Once destabilized, subsequent shocks can more easily terminatethe arrhythmia and restore normal sinus rhythm.

Virtual electrode excitation can be used at local resistiveheterogeneities to depolarize a critical part of the reentry pathway orexcitable gap near the core of reentry. Various pulse protocols for athree-stage atrial cardioversion therapy to terminate atrial arrhythmiasin accordance with aspects of the present invention are contemplated. Inone aspect, the reentry is either terminated directly or destabilized byfar-field pulses delivered in a first and second stage and thenterminated by additional stimuli by near-field pulses delivered in athird stage of the three-stage atrial cardioversion therapy. The lowenergy stimulation can be below the pain threshold and, thus, may causeno anxiety and uncomfortable side effects to the patient. In anotheraspect, a phased unpinning far-field therapy can be delivered inresponse to a detected atrial arrhythmia, with post treatment pacingadministered as a follow-up therapy to the phased unpinning far-fieldtherapy.

To further optimize this low energy method of termination, multipleelectric field configurations can be used to optimally excite theexcitable gap near the core of reentry and disrupt the reentrantcircuit. These field configurations can be achieved by placing severaldefibrillation leads/electrodes into the coronary sinus (with bothdistal and proximal electrodes), the right atrial appendage, and thesuperior venae cavae. In another embodiment, an electrode can be placedin the atrial septum. Electric fields can be delivered between any twoor more of these electrodes as well as between one of these electrodesand the device itself (hot can configuration). In another aspect,segmented electrodes with the ability to selectively energize one ormore of the electrode segments can be used. Modulation of the electricfield vector can then be used to achieve maximum coverage of the entireatria within one set of shock applications or on a trial to trial basis.The optimal electric fields used and the correct sequence of fields canalso be explored on a trial and error basis for each patient.

In another aspect of the present invention, a pain threshold protocol isimplemented for the treatment. The device and a plurality of leads areimplanted into a patient who is sedated or under anesthesia. When thepatient is completely free from the effects of the sedation oranesthetic, the device is instructed to individually interrogate theimplanted leads, with stimulation being activated between both the leadsand also between the can and the leads. The patient is asked to indicatea level of discomfort for each stimulation. The stimulation energy isinitially set at low values and then is increased in a ramp-up mode, andthe patient is asked to indicate when their pain threshold is reached.Default maximum stimulation energy levels previously stored in thedevice are replaced by the custom values determined through thisprotocol, and the device is programmed to restrict therapy to energylevels that are below these custom values.

In another aspect of the present invention, pre-treatment externalinformation from a variety of sources, e.g. an electrocardiogram or amagnetic resonance image of the patient, regarding the likely locationof a reentrant loop can be used to facilitate certain aspects of thetreatment. Such external information can be used to determine thesuitability of a patient for the procedure, vis-a-vis alternatetreatments such as ablation or drug therapy, and to determine leadselection and placement, or determine the initial lead energizingpattern.

In another aspect of the present invention, the morphology of anelectrogram of an arrhythmia can be documented, stored, and compared topreviously stored morphologies. Anatomic location(s) of the reentrycircuit(s) may be determined by the specific anatomy and physiologicalremodeling of the atria, which are unique for each patient. Theembodiment takes advantage of the observation that several morphologiesof atrial arrhythmias tend to occur with higher frequency than others.Optimization of electric field configuration and pulse sequence of thetherapy may be conducted separately for each electrogram morphology andstored in memory for future arrhythmia terminations. When an arrhythmiais detected, it will be determined whether the morphology of theelectrogram of an arrhythmia is known. If it is, the optimized therapystored in memory may be applied to convert that arrhythmia.

In an aspect of the present invention, a method for destabilization andtermination of atrial tachyarrhythmia includes detecting an atrialtachyarrhythmia initiation from sensing of atrial electrical activity,estimating a minimum or dominant arrhythmia cycle length (CL), sensingventricular electrical activity to detect a ventricular R-wave,delivering far-field atrial electrical shocks/stimulation as a pulsetrain from two to ten pulses during one or several cycles of AF/AFl,optionally delivering atrial pacing with CL generally from about 70% toabout 100% of sensed atrial fibrillation cycle length (“AFCL”) minimumvalue, and (a) determining ventricular vulnerable period using R-wavedetection to prevent or inhibit induction of ventricular fibrillation byatrial shock, (b) determining the atrial excitation threshold byapplying electrical shock through different implanted atrialdefibrillation leads and subsequently sensing for atrial activation, (c)determining pain threshold by a feedback circuit that uses informationprovided by the patient during both the implantation and calibrationprocedure, and during the execution of the device learning algorithms,(d) determining the ventricular far-field excitation threshold byapplying electrical shock through different implanted atrialdefibrillation leads and subsequently sensing for ventricularactivation, (e) delivering far-field stimuli to the atria bysequentially delivering several pulses at energies above the atrialexcitation threshold.

In another aspect of the present invention, an implantable cardiactherapy device for treating an atrium in need of atrial defibrillationincludes one or more sensors comprising one or more implanted electrodespositioned in different locations for generating electrogram signals,one or more pacing implanted electrodes positioned in differentlocations for near-field pacing of different atrial sites, one or moreimplanted defibrillation electrodes positioned in different locationsfor far-field delivery of electrical current, and an implantable orexternal device which can be capable to deliver a train of pulses.

In one exemplary embodiment, the implantable device is implanted justunder the left clavicle. This location places the device in approximatealignment with the longitudinal anatomical axis of the heart (an axisthrough the center of the heart that intersects the apex and theinter-ventricular septum). When the electrodes are implanted in thismanner, the arrangement of the device and electrodes is similar inconfiguration to the top of an umbrella: the device constituting theferrule of an umbrella, and the electrodes constituting the tines of theumbrella. The electrodes of the device are energized in sequential orderto achieve electrical fields of stimulation that is similar to“stimulating” the triangles of umbrella fabric, one after the other, ineither a clockwise or counter-clockwise manner or in a custom sequence.In one aspect, a right ventricular lead is positioned as part of theimplantation. In another aspect, no ventricular lead is positioned,removing the need for a lead to cross a heart valve during leadimplantation. Leads may be active or passive fixation.

In another aspect, the device can be fully automatic; automaticallydelivering a shock protocol when atrial arrhythmias are detected. Inanother aspect, the device can have a manual shock delivery; the deviceprompting the patient to either have a doctor authorize the device todeliver a shock protocol, or the device can prompt the patient toself-direct the device to deliver a shock protocol in order to terminatea detected arrhythmia. In another aspect, the device can besemi-automatic; a “bed-side” monitoring station can be used to permitremote device authorization for the initiation of a shock protocol whenatrial arrhythmias are detected.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention may be more completely understood in consideration of thefollowing detailed description of various embodiments of the inventionin connection with the accompanying drawings, in which:

FIG. 1A depicts a schematic posterior view of a human heart andanatomical locations of implantable defibrillation leads and sensingelectrodes;

FIG. 1B depicts a schematic posterior view of a human heart andanatomical locations of implantable defibrillation leads and sensingelectrodes with an optional lead placed in the right ventricle;

FIG. 1C depicts a schematic anterior view of a human heart andanatomical locations of implantable defibrillation leads and sensingelectrodes with leads placed in the right and left atria;

FIG. 2 is a flow chart illustrating a treatment method of an embodimentof the present disclosure;

FIG. 3A is a photograph of a preparation of fluorescent optical mappingof the posterior atria during ACh-induced AFl and AF in a Langendorffperfused rabbit heart with a photodiode array optical mapping field ofview;

FIG. 3B depicts activation maps and optical action potentials (OAP)during AFL and AF of FIG. 3A;

FIG. 4A is a photograph of a preparation of fluorescent optical mappingof the right atrial endocardium during ACh-induced AFl and AF in thecanine isolated atria with a photodiode array optical mapping field ofview;

FIG. 4B depicts activation maps and OAPs during AFL and AF of FIG. 4A;

FIG. 5A depicts a simplified schematic posterior view of a human heart,anatomical locations of implantable defibrillation leads and electrodes,and the direction of a first shock/pulse train;

FIG. 5B depicts a simplified schematic posterior view of a human heart,anatomical locations of implantable defibrillation leads and electrodes,and the direction of a second shock/pulse train;

FIG. 5C depicts a simplified schematic posterior view of a human heart,anatomical locations of implantable defibrillation leads and electrodes,and the direction of a third shock/pulse train;

FIG. 5D depicts a simplified schematic anterior view of a human heart,anatomical locations of implantable defibrillation leads and electrodes,and directions of another shock/pulse train;

FIG. 6 depicts a flow chart illustrating a treatment method of anembodiment of the present disclosure;

FIG. 7 depicts a simplified schematic view of a human heart showingpotential locations of arrhythmias;

FIG. 8 provides a summary of shock amplitudes for six isolated canineright atria experiments in vitro;

FIG. 9 provides a listing of potential electric field sequences fortherapy provided to the regions in FIG. 7 by electrodes positioned asshown in FIGS. 5A, 5B and 5C;

FIG. 10 depicts an embodiment of the FIG. 2 step of applying stimulationin the form of a three-stage cardioversion therapy;

FIG. 11 depicts an embodiment of a stimulation waveform of thethree-stage cardioversion therapy of FIG. 10;

FIG. 12 depicts an embodiment of a first, unpinning stage of thewaveform of FIG. 11;

FIG. 13 depicts an embodiment of a second, anti-repinning stage of thewaveform of FIG. 11;

FIG. 14 depicts an embodiment of a third, extinguishing stage of thewaveform of FIG. 11;

FIG. 15 depicts another embodiment of the FIG. 2 step of applyingstimulation in the form of a three-stage cardioversion therapy;

FIG. 16 depicts an embodiment of a stimulation waveform of thethree-stage cardioversion therapy of FIG. 15;

FIG. 17 depicts yet another embodiment of the FIG. 2 step of applyingstimulation in the form of a three-stage cardioversion therapy;

FIG. 18 depicts yet another embodiment of a stimulation waveform of thethree-stage cardioversion therapy of FIG. 17;

FIGS. 19A and 19B are block diagrams depicting of an embodiment of athree-stage cardioversion therapy device, and the therapy circuitrythereof, respectively;

FIGS. 20A-20H depict various portions of the therapy circuitry of thedevice of FIGS. 19A and 19B, in greater detail, according to variousembodiments;

FIG. 21 depicts an EKG waveform of a canine subject receiving thethree-stage cardioversion therapy of FIG. 10;

FIG. 22 depicts an EKG waveform of a canine subject receiving thethree-stage cardioversion therapy of FIG. 16;

FIG. 23 depicts four bar charts summarizing the energy applied duringvarious applications of one-, two-, and three-stage therapy across threedifferent vectors;

FIG. 24 depicts another embodiment of a three-stage therapy asimplemented in a canine model;

FIGS. 25A-D depict a lead placement used to implement the three-stagetherapy of FIG. 24 in the canine model;

FIG. 26 depicts a sample comparison of atrial DFTs and correspondingelectro-cardiograms of a single-biphasic shock and the three-stagetherapy of FIG. 24; and

FIG. 27 depicts another sample comparison of atrial DFTs of asingle-biphasic shock and the three-stage therapy of FIG. 24.

While the invention is amenable to various modifications and alternativeforms, specifics thereof have been shown by way of example in thedrawings and will be described in detail. It should be understood,however, that the intention is not to limit the invention to theparticular embodiments described. On the contrary, the intention is tocover all modifications, equivalents, and alternatives falling withinthe spirit and scope of the invention as defined by the appended claims.

DETAILED DESCRIPTION

Embodiments of the present disclosure are based on a low-voltage phasedunpinning far-field therapy together with near-field therapy that formsthe three-stage atrial cardioversion therapy for destabilizing andsubsequently terminating anatomical reentrant tachyarrhythmias. Asignificant reduction in the energy required to convert an atrialarrhythmia can be obtained with this unpinning, anti-repinning and thenextinguishing technique compared with conventional high-energydefibrillation, thus enabling successful cardioversion without exceedingthe pain threshold of a patient.

The anatomical structure of cardiac tissue can be inherentlyheterogeneous. These syncytial heterogeneities of even modestproportions can represent a significant mechanism contributing to thefar-field excitation process. Fishier, M. G., Vepa K., SpatiotemporalEffects of Syncytial Heterogeneities on Cardiac Far-field Excitationsduring Monophasic and Biphasic Shocks, Journal of CardiovascularElectrophysiology, 1998, 9(12): 1310-24, which is incorporated herein byreference.

For purposes of the present application, the term “near-field,” canrelate to effects that are in close proximity to stimulatingelectrode(s), i.e., distances are restricted by several space constants(lambda) of cardiac tissue, which is typically up to severalmillimeters. Near-field effects can be strongly dependent upon distancefrom the electrodes. The term “far-field,” on the other hand, can relateto effects that are generally independent or less dependent upondistance from the electrodes. They can occur at distances that are muchgreater than the space constant (lambda).

Applying far-field low energy electric field stimulation in a range oftime- and frequency-domains can interrupt and terminate the reentrantcircuit by selectively exciting the excitable gap near the core ofreentry. High frequency far-field electric stimulation has significantlyhigher defibrillation success compared to near-field ATP. The reentrantcircuit can be anchored at a functionally or anatomically heterogeneousregion, which constitutes the core of reentry. The virtual electrodetheory of myocardial excitation by electric field predicts that areasnear the core will experience greater polarization in response to anapplied electric field compared with the surrounding, more homogeneoustissue. Various shock protocols to terminate atrial arrhythmias arecontemplated. Thus, in one aspect, the region near the core of reentrycan be preferentially excited with very small electric fields todestabilize or terminate anchored reentrant circuits. Once destabilized,subsequent shocks can more easily drive the rotors away to the boundaryof atrial tissue and restore normal sinus rhythm.

In traditional high-voltage defibrillation therapy, a truncatedexponential biphasic waveform has a lower defibrillation energy ascompared to monophasic shocks. However, in the case of phased unpinningfar-field therapy (“PUFFT”), the use of multiple monophasic versusmultiple biphasic waveforms was recently found to be more effective interminating ventricular tachycardias in a rabbit model. This differencewas thought to exist because optimal biphasic defibrillation waveformsmay not produce VEPs because of an asymmetric effect of phase reversalon membrane polarization. Efimov, I. R., Cheng, Y., Van Wagoner, D. R.,Mazgalev, T., Tchou, P. J., Virtual Electrode-Induced Phase Singularity:A Basic Mechanism of Defibrillation Failure, Circulation Research, 1998,82(8): 918-25, which is incorporated herein by reference. YEP isdiscussed further in Efimov, I. R., Cheng, Y. N., Biermann, M., VanWagoner, D. R., Mazgalev, T. N., Tchou, P. J., Transmembrane VoltageChanges Produced by Real and Virtual Electrodes During MonophasicDefibrillation Shock Delivered by an Implantable Electrode, Journal ofCardiovascular Electrophysiology, 1997, 8(9): 1031-45; Cheng, Y. N.,Mowrey, K. A., Van Wagoner, D. R., Tchou, P. J., Efimov, I. R., VirtualElectrode-Induced Reexcitation: A Mechanism of Defibrillation,Circulation Research, 1999, 85(11): 1056-66; and Fishier, M. G.,Syncytial Heterogeneity as a Mechanism Underlying Cardiac Far-FieldStimulation During Defibrillation-Level Shocks. Journal ofCardiovascular Electrophysiology, 1998, 9(4): 384-94, all of which areincorporated herein by reference.

The ventricular defibrillation threshold (“DFT”) can be significantlydecreased by an orthogonally rotating current field. Tsukerman, B. M.,Bogdanov, Klu, Kon, M. V., Kriukov, V. A., Vandiaev, G. K.,Defibrillation of the Heart by a Rotating Current Field, Kardiologiia,1973, 13(12): 75-80, which is incorporated herein by reference. Bycombining two sequential shocks with a rotating electrical field vector,the atrial defibrillation threshold (“ADFT”) of the standard leadconfiguration (right atrium to distal coronary sinus) can besignificantly reduced when followed by a second shock along the atrialseptum delivered between electrodes in the proximal coronary sinus andeither the SVC or Bachmann's bundle. Zheng, X., Benser, M. E., Walcott,G. P., Smith, W. M., Ideker, R. E., Reduction of the Internal AtrialDefibrillation Threshold with Balanced Orthogonal Sequential Shocks,Journal of Cardiovascular Electrophysiology, 2002; 13(9): 904-9, whichis incorporated herein by reference. The ADFT can be further reducedwith balanced sequential shocks.

Virtual electrode excitation can be used at local resistiveheterogeneities to depolarize a critical part of the reentry pathway orexcitable gap near the core of reentry. Thus, reentry can be terminateddirectly or destabilized and then the reentry can be terminated byadditional stimuli. This technique can be exploited in an implantable orexternal device, which, upon sensing an atrial tachyarrhythmia, canapply the low energy stimulation at several different timing intervalsuntil the correct timing can be achieved and the arrhythmia can beterminated. This “trial and error” approach can be used, as atrialarrhythmias are not immediately life threatening. Also, the low energystimulation can be expected to be below the pain threshold and thus maycause no anxiety and uncomfortable side effects to the patient.

To further optimize the low energy method of termination, multipleelectric field configurations can be used to optimally excite theexcitable gap near the core of reentry and disrupt the reentrantcircuit. Referring to FIGS. 1A and 1B, these field configurations can beachieved by placing several implantable defibrillation electrodes 11into the proximal 12 and distal 13 coronary sinus (“CS”), the rightatrial appendage (“RAA”) 14, and the superior venae cavae (“SVC”) 15. Inone aspect, a right ventricular lead is positioned as part of theimplantation (FIG. 1B). In another aspect, no ventricular lead ispositioned (FIG. 1A), removing the need to cross a heart valve duringlead implantation. Leads may be active or passive fixation. As can beseen from FIG. 1, no leads are placed in the left side of the heart,thus reducing the time required for implantation.

Electric fields can be delivered between any two of these electrodes aswell as between one of these electrodes and the device itself 16 (hotcan configuration). Modulation of the electric field vector can be usedto achieve maximum coverage of the entire atria and to maintain optimalVirtual Electrode Polarization pattern through the entire cycle ofarrhythmia in order to depolarize the maximum area of excitable gaps.The optimal electric fields used and the correct sequence of fields canalso be explored on a trial and error basis for each patient or can beestimated based on external information regarding potential sites of thereentrant circuits, or can be based on a combination of both.

Referring also to FIG. 1C, a first electrode 11 a is placed in the rightatrium, and a second electrode 11 b is placed in the left atrium fordelivery of atrial defibrillation therapy. Although only two electrodes11 a and 11 b are depicted, it will be understood that additionalelectrodes and corresponding leads may also be implanted, including aventricular sensing electrode, as well as other electrodes depicted anddescribed with respect to FIGS. 1A and B.

FIGS. 5A, 5B and 5C together depict a clock-wise rotation of the vectorsof a series of three consecutive far field unpinning shocks. In thisexample, multiple, monophasic shocks can be applied with intervals as afunction of arrhythmia cycle length. In one example, the far fieldunpinning shocks can be square waves, 10 ms in duration of which thevoltage and vectors will be varied to determine minimum terminationvoltage. In other embodiments, the far field unpinning shocks or pulsesmay be rounded, staggered, ascending, descending, biphasic, multiphasic,or variations thereof.

In FIG. 5A a first far field unpinning shock 40 is applied between theelectrode located in the right atrial appendage (b) and the device (a).In FIG. 5B a second far field unpinning shock 42 is applied between theelectrode located distal in the coronary sinus (e) and the electrodelocated in the superior venae cavae (c). In FIG. 5C a third far fieldunpinning shock 44 is applied between the device (a) and the electrodelocated proximal in the coronary sinus (d).

Referring also to FIG. 5D, shocks may also be applied between electrodes11 a in the right atrium and 11 b in the left atrium, as indicated bythe bi-directional arrow depicted. Although only two electrodes aredepicted, and only a first electrical field vector from electrode 11 ato 11 b, and a second vector from electrode 11 b to 11 a are depicted,it will be understood that any series of shocks or pulses may be appliedbetween electrodes 11 a and 11 b and other placed electrodes, includingbetween electrodes 11 a/11 b and the device, to deliver a series ofshocks between electrodes and the device as depicted and described abovewith respect to FIGS. 5A to 5C.

While a number of lead and electrode placements are described above,generally speaking, an optimal electrode configuration is one thatmaximizes current density across the atria, particularly in the regionwhere the arrhythmia arises, thereby maximizing depolarization in theatrial region originating the arrhythmia.

An algorithm may be used for treatment of AFl and AF. To determinewhether the atria are in flutter or fibrillation, the device can firstestimate the CL of arrhythmia. For example, if the average atrialcardiac CL is less than 250 ms, but greater than 150 ms, the atria areconsidered to be in AFl. The distinguishing characteristics of AF andAFl vary on a patient-to-patient basis and thus these CL parameters canbe programmable based on patient's need. Examples of distinguishing AFfrom AFl are described in U.S. Pat. No. 5,814,081, which is incorporatedherein by reference. In addition, an algorithm can be used tocharacterize and categorize morphologies of atrial electrogram in orderto use this information for patient-specific and morphology-specificoptimization of phased unpinning far-field therapy.

An optimum time to apply the phased unpinning far-field therapy relativeto the cardiac cycle may be determined from the ventricular sensingelectrodes including RV or far-field R-wave detection. Examples offinding unsafe times for far-field shock are also described in U.S. Pat.No. 5,814,081.

Other timing considerations, particularly with respect to phase or stagedurations, may be determined in whole or in part by characteristics ofthe sensed atrial fibrillation. As will be described below, whileventricular activity, such as R-wave characteristics, may be used todetermine an overall therapy timing, such as a maximum window of timefor therapy delivery, an AF CL may determine a particular phase durationwithin that window of time.

Learning algorithms may also used to optimize therapy on subsequentterminations. Once the optimal timing and field settings are achievedfor a patient to terminate an atrial tachyarrhythmia, these settings arethe starting point for termination of the next bout of AFl/AF.

Because AFl/AF are not immediately life-threatening arrhythmias, therapycan be optimized using a trial and error approach combined with learningalgorithms to tailor therapy for each patient. The optimization includestwo objectives: (a) terminating arrhythmia and (b) avoiding intensitiesassociated with pain.

As described above, the pain threshold depends on many factors,including autonomic tone, presence of drugs, location of electrodes andshock waveforms. A value of 0.1 J has been reported by Ladwig, K. H.,Marten-Mittag, B., Lehmann, G., Gundel, H., Simon, H., Alt, E., Absenceof an Impact of Emotional Distress on the Perception of IntracardiacShock Discharges, International Journal of Behavioral Medicine, 2003,10(1): 56-65, which is incorporated herein by reference, as the energyvalue where pain and/or discomfort is first generally experienced.However, it can be different from patient to patient. Thus, a real-timefeedback to the patient can be provided in estimating the pain thresholdduring either the implantation or calibration of the device or duringexecution of the optimizing learning algorithms.

Referring now to FIG. 6, a pain threshold protocol 200 is described. Anatrial arrhythmia treatment device is implanted in a patient, who issedated or under anesthesia, during a surgical procedure 202. Theimplanted device includes an implantable therapy generator and at leasttwo leads operably connected to the implantable therapy generator, eachlead having at least two electrodes adapted to be positioned proximatethe atrium of a heart of the patient. At a time after completion of thesurgical procedure, when the patient is fully conscious and completelyfree from the effects of the sedation or anesthetic, the atrialarrhythmia treatment device is configured 204. The device is instructedto apply a PUFFT treatment 206, via a far field configuration of theelectrodes, to the patient in response to detection of an atrialarrhythmia, the PUFFT treatment having a first set of therapyparameters. The patient then provides an indication of pain sensation inresponse to the PUFFT 208. An assessment is made of the effectiveness ofthe PUFFT treatment of the atrial arrhythmia 210. An evaluation is maderegarding the effectiveness of the PUFFT treatment and the indication ofpain sensation 212. In response to both the indication of pain, and ofthe assessment of the effectiveness of the treatment, an adjustment ismade to at least one of the set of therapy parameters and the far fieldconfiguration of the electrodes 214. Steps 206 to 212 are repeated untila set of therapy parameters and a far field configuration of theelectrodes have been determined that provide an effective treatment ofthe atrial arrhythmia for the patient at a pain sensation that istolerable to the patient. The atrial arrhythmia treatment device is thenprogrammed with the set of therapy parameters and the far fieldconfiguration of the electrodes 216 as determined from steps 206-214 tobe used by the device in automatically treating an atrial arrhythmiadetected by the device.

Referring to FIG. 2, upon device implantation, several measurements arefirst made (P101-P103). The field excitation thresholds for both atrialand ventricular excitation are measured from each lead combination asdescribed previously (P101). These values serve as the minimum andmaximum stimulation strengths, respectively, and can be testedperiodically by the device for changes. Stimulation strengths can alsobe increased until the patient senses the shock and feels pain. Apatient feedback mechanism can be employed to register this maximumshock amplitude, which corresponds to pain threshold for this particularsite. These minimum and maximum values outline the operating range ofthe device.

After implantation, the device enters a sensing mode (21) to sense foratrial tachyarrhythmias. When an arrhythmia is sensed, the minimumAFl/AF CL can be determined from all sensing electrodes. The minimumAFl/AF CL can then be used to calculate the stimulus frequency (23 b),which may range from about 20% to about 100% of the minimum AFl/AF CL.As will be described further below, in some embodiments, a stimulusfrequency is determined based on a range of 70% to 100% of AFl/AF CL,such that the time between shocks, or pulses, of a particular therapyphase or stage ranges from 70% to 100% of AFl/AF CL. The device thendetermines if the arrhythmia is the first bout of AFl/AF afterimplantation (24). If so, a default combination of stimulus parameterscombined with the minimum stimulation strengths as previously measuredcan be used for the first defibrillation trial (P103) and (26). Thecombination of stimulus parameters (23) can include: number of stimuli(23 a), frequency of stimuli (23 b), number of electric fieldconfigurations (23 c), sequence of electric field configurations (23 d),field strength (23 e), waveform morphology (23 f), and the inter-stagedelay. The default combination of parameters can be based onexperimental evidence found in animal models of AFl/AF, previousexperience with this technology, or results of patient specific testingat the time of implant. If it is not the first bout of AFl/AF afterimplant, stored parameters from the previous stimulus application can beused for the first defibrillation trial (25)-(26). In some embodiments,to avoid inducing a ventricular arrhythmia, the device then waits forthe next sensed R-wave to deliver the atrial defibrillation therapy. Theappropriate stimulus parameters are then delivered (28).

After the defibrillation trial, which may include multiple therapystages, sensing can then be employed again to determine if the trial wassuccessful (29). If the trial was unsuccessful, and the duration ofAFl/AF has not exceeded the maximum allowed duration (30), the stimulusparameters (23) are varied and another defibrillation trial can beperformed (25)-(29). Because of the large number of stimulus parameters(23), a neural network can be employed within the device to control thesequence and optimization of the parameters. The defibrillation trialscontinue (25)-(29) until the arrhythmia is terminated or until themaximum duration of AFl/AF is reached (30). Because prolonged AFl/AF canpromote pathological remodeling of atria (atrial fibrillation begetsatrial fibrillation), blood clotting and increase a patient's risk ofstroke along with other complications, a higher energy rescue shock (31)can be delivered if necessary and low energy optimization can becontinued upon the next bout of AFl/AF.

If a successful combination of parameters is found, the stimulusparameters can be saved (36), (25) and employed upon the next bout ofAFl/AF. If a particular combination of stimulus parameters is found tobe successful for many bouts of AFl/AF (i.e., >5 successfulterminations) (33), the device can enter a “continual optimizationalgorithm” (34) to determine if the energy can be further decreased. Thestimulus parameters can be varied at a lower energy (35), (23) to try tofind another successful combination. If another such combination is notdetermined, the device can return to using the successful combination.

In one embodiment, the morphology of an arrhythmia's electrogram can bedocumented, stored, and compared to previously stored morphologies.Anatomic location(s) of the reentry circuit(s) are determined by thespecific anatomy and physiological remodeling of the atria, which areunique for each patient. Thus, the morphologies can reveal the specificanatomic locations of the reentry circuits. Optimization of the pulsesequence of the therapy can be conducted separately for each electrogrammorphology and stored in memory for future arrhythmia terminations.

Referring to FIG. 7, various locations 302 where reentry circuits may beanchored are depicted. The locations 302 have been divided into fivezones 310, 320, 330, 340 and 350 indicated by the dashed lines. In oneembodiment, a default therapy sequence can be initiated for reentrycircuits located in each zone. For example, if the morphology of thearrhythmia indicates that the reentry circuit is located in zone 310,the sequence of electric fields applied might begin between electrode(b) and electrode (a) (on the device) as depicted in FIG. 5A. Thesequence may then continue with an electric field between electrode (e)and electrode (c) (FIG. 5B) followed by one between electrode (a) andelectrode (d) (FIG. 5C). The table in FIG. 9 provides one example ofpotential default therapy sequences for each zone 310, 320, 330, 340,and 350 in FIG. 7. If the default therapy sequence in a given zone failsto terminate the arrhythmia, additional therapy sequences maysubsequently be applied.

Because this device, in certain embodiments, can deliver a series ofelectric field stimuli in rapid succession, traditional implantablepulse generators, such as those normally used in ICDs generally may beinadequate for the device. Traditional implantable pulse generatorsemploy a charging period (on the order of seconds) to charge acapacitor, then rapidly discharge the capacitor to apply the shock.Before the next shock application, the capacitor may need to be chargedagain. In this device, several low energy far field unpinningshocks/pulses (two-ten) can be applied in rapid succession (in someembodiments ranging from 10-100 ms apart, which in some embodiments isdetermined by the AFl/AF CL) for each unpinning shock.

The implantable pulse generator according to one type of embodiment ofthis device can include several smaller capacitors that charge before orduring the defibrillation trials. For each stimulus delivered, a singlecapacitor discharges with the appropriate amount of energy followedsequentially by a discharge from another capacitor until the appropriatenumber of stimuli is delivered. The capacitors can all be chargedsimultaneously before the entire defibrillation trial or, alternatively,the capacitors can be charged sequentially in groups, or individually.In one example implementation, capacitors which are used for unpinningshocks that appear later in the defibrillation trial are charged whileother unpinning shocks are applied earlier in the trial via othercapacitors, which were charged previously. In a related example, acapacitor that is used for an earlier unpinning shock is re-chargedduring a subsequent one or more shock of the trial, and is furtherre-used for a later unpinning shock of the same trial. This latterexample is facilitated in embodiments where the power supply is capableof sufficient current drive to charge the capacitors in sufficient timeto permit their re-use within the same trial.

In a related embodiment, the device uses multiple capacitors for storingthe electrotherapy energy, except that, unlike the example embodimentdescribed above, each capacitor has sufficient energy storage to providemore than a single shock in the sequence.

In order to produce the appropriate stimuli across the appropriate leadconfiguration, a fast-switching network can be employed to switch thedischarged energy between the different capacitors as well as switchingthe applied energy to the correct electrodes. The pretreatment of pulsesis described further in U.S. Pat. Nos. 5,366,485 and 5,314,448, both ofwhich are incorporated herein by reference.

Experimental Results

Referring to FIGS. 3A and 3B, a series of experiments were conducted inwhich the posterior epicardium of the right and left atria (RA and LA)and the pulmonary vein (PV) region of Langendorff-perfused rabbit hearts(n=9) were simultaneously optically mapped in control and during AChperfusion (2.5-100 .mu.M). In FIG. 3A, the fluorescent optical mappingof the posterior atria during ACh-induced AFl and AF in aLangendorff-perfused rabbit heart with a photodiode array opticalmapping field of view is shown wherein (1) the location of the origin ofa normal sinus rhythm heart beat is indicated by a blue/purple circle,(2) the narrow gray oval indicates the line of intercaval conductionblock, as identified during normal sinus rhythm and during pacing, thesite of resistive heterogeneity, which is highly likely to serve as apinning site for a reentry circuit during atrial flutter or atrialfibrillation, (3) dashed black lines with arrows indicate the locationand direction of reentrant circuits, and (4) dashed white lines indicatevessels that have been ligated. In FIG. 3B, the activation maps andoptical action potentials (OAP) during AFl and AF of FIG. 3A are shown,wherein (1) the narrow gray oval indicates the line of intercavalconduction block, the site of resistive heterogeneity, and (2) dashedwhite lines with arrows indicate the location and direction of reentrantcircuits, and wherein isochronal maps are depicted in 4.0 ms steps.

Arrhythmias were provoked by a single premature stimulus or burstpacing. Low-energy shocks were delivered from two large mesh electrodeslocated on either side of the heart, oriented parallel to the verticalaxis of the heart. To prevent or inhibit motion artifacts, Blebbistatin(BB) was used. BB is a highly specific inhibitor of myosin TI isoforms.Under control conditions, AF was not induced, and sustained AFl wasinduced only in 1 heart. Ach depressed the sinus rhythm and provokedatrial premature beats (“APBs”) with a coupling interval of 93.+−.7 msfrom the RA appendage, superior PVs and inferior vena cava regions. APBsresulted in spontaneous AF in 3 hearts. In 8 hearts, a single prematurestimulus or burst pacing induced sustained AFl and AF (>10 min) at7.+−.2 .mu.M and 20.+−.8 .mu.M ACh, respectively.

Referring again to FIG. 3B, AFl and AF were maintained by a singlemacroreentrant circuit around a region of conduction block between theSVC and IVC (CL=79.+−.10 ms) or multiple reentry circuits (CL=48.+−.6ms), respectively. In most cases, AF was associated with mother rotormicroreentry in the pectinate muscles of RA (75%) and/or LA (25%). FIG.3B depicts an example of activation during AF. AF was associated with astable mother rotor (figure-of-eight) in the RA appendage. Rarely,several complete rotations of an additional rotor were observed in theLA, but this rotor was generally not sustained.

To terminate the arrhythmias, monophasic five ms shocks were deliveredfrom external mesh electrodes. Either a single shock was appliedthroughout various phases of AFl or multiple (three-five) shocks wereapplied within one AFl CL. Anti-tachycardia pacing (ATP, 8 pulses,50-100% of AFl CL) was also applied from the RA appendage electrode orthe IVC region electrode.

A statistically significant phase window was found in which singleshocks terminated AFl with a defibrillation threshold (DFT) of0.9.+−.0.4 V/cm. Termination of AFl was preceded by a short (<1 sec) runof AF in 30% of cases, which are demonstrated examples ofdestabilization of reentry before its complete termination. Multipleshocks had lower termination strength of 0.7.+−.0.1 V/cm. ATP aloneterminated AFl in only 4 of the 6 hearts on which it was applied with15% of terminations preceded by AF and 11% of applications resulting insustained AF. Conventional time-independent monophasic shocks terminatedsustained AF with a minimum strength 4.7.+−.0.9 V/cm only. The lowerefficacy of ATP suggests that low-energy field stimulation may be analternative to ATP for the treatment of AFl.

Experimental protocols were transferred from the rabbit model to thecanine AF model. AFl or AF was electrically induced in isolated,coronary-perfused canine right atria (n=7) in the presence ofacetylcholine (3.8.+−.3.2 .mu.M). CL of AFl and AF was 130.7.+−.30.7 msand 55.6.+−.7.9 ms, respectively. Referring to FIGS. 4A and 4B, usingoptical mapping (16.times.16 photodiode array), AFl and AF weredetermined to be maintained by single macroreentrant circuits around thesinoatrial node region or multiple reentry circuits, respectively. FIG.4A shows a preparation of fluorescent optical mapping of the rightatrial endocardium during Ach-induced AFl and AF in the canine isolatedatria with a photodiode array optical mapping field of view, wherein (1)the sin .theta.-atrial node, which is a resistive heterogeneity, andoften serves as a pinning location for a reentry circuit during atrialflutter is indicated by a dark blue/purple oval, (2) dashed white lineswith arrows indicate a reentry circuit during atrial flutter, and (3)dashed black lines with arrows indicate a reentry circuit during atrialfibrillation (which is pinned to another resistive heterogeneity). FIG.4B shows activation maps and OAPs during AFL and AF wherein (1) dashedwhite lines with arrows indicate a reentry circuit during atrialflutter, and (2) dashed black lines with arrows indicate a reentrycircuit during atrial fibrillation (which is pinned to another resistiveheterogeneity). It can be seen that AF reentry cores were located atfunctional and anatomical heterogeneities in the pectinate muscles andSVC/IVC regions. Single or multiple monophasic 10 ms shocks were appliedfrom parallel mesh electrodes in the tissue bath using the rabbitexperimental setup.

The far-field diastolic threshold of excitation was reached at0.14.+−.0.12 V/cm (0.005+0.0001 J) when supra-threshold virtual cathodeswere induced at local resistive heterogeneities. Single-shock ADFT wassignificantly lower for AFl vs. AF (0.2.+−.0.06 vs. 7.44.+−.3.27 V/cm,or 0.018.+−.0.001 vs. 2.6.+−.0.78 J; p<0.05). However, application of 2or 3 pulses delivered at an optimal coupling interval between pulsesallowed significant reduction of the ADFT for AF: 3.11.+−.0.74 V/cm and3.37.+−.0.73 V/cm, or 0.44.+−.0.04 and 0.48.+−.0.03 J for 2 and 3pulses, respectively (p<0.05 vs. 1 pulse). Coupling intervaloptimization was performed in the range of 20-190% of the AF CL. Optimalcoupling interval was 87.3.+−.18.6% and 91.3.+−.17.9% for two and threepulses, respectively. The table in FIG. 8 provides the summary of theseresults collected in six canine atrial preparations.

Moreover, low voltage shocks (0.1-1 V/cm) converted AF to AFl. Thus,atrial defibrillation or cardioversion may best be achieved by amulti-step process that includes: (a) conversion of AF to AFL, and (b)termination of AFl. Both steps are achieved with multiple pulses withenergy ranging from 0.02-0.1 J.

Similar ADFT values for AF and AFl were found in both models,demonstrating the relevance of the rabbit model for experiments in dogsand further applications. Lower ADFTs can be obtained when multiplefield directions are used, as well as when appropriately timed shocks ormultiple shocks are used.

The method described above is exemplary of a method in accordance withone aspect of the present invention. The methods above may beaccomplished by an internal, implanted device. The methods above may beaccomplished using any number and configuration of electrodearrangements, such as endocardial, epicardial, intravenous, implantable,or external, or any combination thereof, to deliver electrical cardiacstimulation in accordance with the present invention. Multiple pathelectrode configurations as contemplated for use with some embodimentsof the present as shown, for example, in U.S. Pat. Nos. 5,306,291 and5,766,226, the disclosure of each of which are incorporated herein byreference.

It is contemplated that the method of the present invention can beutilized together with, or separate from, other pacing anddefibrillation therapies. For example, the present invention can beimplemented as part of an ICD where a high voltage defibrillation shockcan be delivered in the event that the method of the present inventionis unable to successfully convert a cardiac arrhythmia. Alternatively,the present invention could be implemented as part of a conventionalpacemaker to provide for an emergency response to a VTNF condition inthe patient that would increase the chances of patient survival.

The methods of the present invention also contemplate the use of anynumber of arrangements and configurations of waveforms and waveshapesfor the electrical stimulation pulse(s). Known monophasic, biphasic,triphasic and cross-phase stimulation pulses may be utilized. In oneembodiment, the present invention contemplates the use of an ascendingramp waveform as described in the article Qu, F., Li, L., Nikolski, V.P., Sharma, V., Efimov, I. R., Mechanisms of Superiority of AscendingRamp Waveforms: New Insights into Mechanisms of Shock-inducedVulnerability and Defibrillation, American Journal of Physiology—Heartand Circulatory Physiology, 2005, 289: H569-H577, the disclosure ofwhich is incorporated herein by reference.

The methods of the present invention also contemplate the use of anynumber of arrangement and configurations for the generation of thephased unpinning far field electrical stimulation pulse(s). Whileconventional high voltage capacitor discharge circuitry may be utilizedto generate the lower energy stimulation pulse(s) in accordance with thepresent invention, it is also expected that alternative arrangementscould be utilized involving lower voltage capacitor arrangements, suchas stacked, switched or secondary capacitors, rechargeable batteries,charge pump and voltage booster circuits as described, for example, inU.S. Pat. Nos. 5,199,429, 5,334,219, 5,365,391, 5,372,605, 5,383,907,5,391,186, 5,405,363, 5,407,444, 5,413,591, 5,620,464 and 5,674,248, thedisclosures of each of which are incorporated herein by reference.Generation of the staged/phased unpinning far field therapy inaccordance with embodiments of the present invention can be accomplishedby any number of methods, including known methods for generating pacingpulses. Similarly, any number of known techniques for cardiac arrhythmiadetection may be used in accordance with the method of the presentinvention.

Three-Stage Atrial Cardioversion Therapy

In accordance with one embodiment the PUFFT therapy is delivered as partof a three-stage atrial cardioversion therapy. As shown in FIG. 10, inone embodiment the therapy (28) that is delivered by the method shown inFIG. 2 comprises a three-stage atrial cardioversion therapy delivered tothe patient in response to detection of an atrial arrhythmia, thethree-stage atrial cardioversion therapy having a set of therapyparameters and having a first stage (400) and a second stage (402)delivered via a far field configuration of the electrodes and a thirdstage (404) delivered via a near field configuration of the electrodes.It will be understood that “three stage” therapy refers to allvariations of therapies of the claimed invention that include at leastone set of first-stage pulses, at least one set of second-stage pulses,and at least one set of third-stage pulses. It will also be understoodthat “multi-therapy” includes multiple three-stage therapies, whereinthe atrial arrhythmia may be reevaluated between three-stage therapyimplementations.

Referring to FIG. 11, a combined representation of all three of thestages of the three-stage atrial cardioversion therapy is shown. A firststage (400) is applied for unpinning of one or more singularitiesassociated with an atrial arrhythmia. A second stage (402) is appliedfor anti-repinning of the one or more singularities associated with theatrial arrhythmia. A third stage (404) is applied for extinguishing ofthe one or more singularities associated with the atrial arrhythmia.

In various embodiments, the first stage (400) has at least two and lessthan ten atrial cardioversion pulses of 10 volts to 100 volts. Whiledepicted as biphasic, first stage (400) pulses may alternativelycomprise monophasic or other custom-configured pulses. In an embodiment,the first stage (400) includes pulses ranging from 10 volts to 30 volts.Pulse duration may be approximately 3-4 milliseconds in someembodiments, or, more generally, of equals to or less than 10milliseconds in various other embodiments, with a pulse couplinginterval ranging from 20 to 50 milliseconds. In some embodiments, thefirst stage (402) has a total duration of less than two cycle lengths ofthe atrial arrhythmia.

In some such embodiments, the total duration may be determined as apercentage of the atrial fibrillation cycle length (AF CL), which in anembodiment ranges from 30 to 50% of a single AF CL. In otherembodiments, the total duration of the first stage (402) may be greaterthan two cycle lengths of the atrial arrhythmia. The first stage mayalso generally be delivered within a ventricular refractory period. Inan alternative embodiment, some first stage (402) pulses are deliveredwithin the ventricular refractory period, and some without. In such anembodiment, individual or total pulse energy delivered within theventricular refractory period may exceed the ventricular capturethreshold in some cases, but those outside the ventricular refractoryperiod would not, so as to avoid inducing ventricular fibrillation. Inone embodiment, the energy of each biphasic atrial cardioversion pulseis less than 0.1 joules.

In an embodiment, an interstage delay (II) of 50 to 400 millisecondsprecedes the second stage (402), though in other embodiments, interstagedelay II may be shorter or longer, such as 100 to 400 milliseconds.

In some embodiments, the second stage (402) has at least five and lessthan ten far field pulses of less than ventricular far-field excitationthreshold (2 to 10 volts). Because second stage (402) is not directlysynched to the R wave, pulse voltage and energy are generally kept lowenough to minimize the risk of ventricular capture, though high enoughto capture the atria. In an embodiment, pulse energy may beapproximately equal to 1.5 times the energy needed to capture the atria.Though depicted as monophasic pulses, second stage (402) may comprisebiphasic, monophasic or another non-traditional configuration. In anembodiment, second-stage pulse duration ranges from 5 ms to 20milliseconds with a pulse coupling interval ranging from 70% to 100% ofthe cycle length of the atrial arrhythmia.

An interstage delay (12) of between 50 to 400 milliseconds precedes thethird stage (404), though in other embodiments, interstage delay 12 maybe shorter or longer, such as 100 to 400 milliseconds.

In some embodiments, the third stage (404) has at least five and lessthan ten near field pulses, which may be biphasic, monophasic or ofanother non-traditional configuration, of less than 10 volts with apulse duration of more than 0.2 and less than 5 milliseconds and a pulsecoupling interval of 70 to 200% of the cycle length of the atrialarrhythmia. The three-stage atrial cardioversion therapy is delivered inresponse to detection of the atrial arrhythmia with each stage (400,402, and 404) and in some embodiments, without confirmation ofconversion of the atrial arrhythmia until after delivery of the thirdstage (404). Generally, as with second stage (402), enough energy shouldbe applied so as to capture the heart with the pacing energy while stillhaving enough energy margin to assure atrial capture.

Referring to FIG. 12, an embodiment of first stage (400) is shown. Inthis embodiment, each of four biphasic cardioversion pulses is deliveredfrom a separate output capacitor arrangement where an H-bridge outputswitching arrangement reversals the polarity of the far-field electrodesat some point during the discharge of the output capacitor arrangement.In alternate embodiments, few output capacitor arrangements may be usedwhere later cardioversion pulses are delivered from the same outputcapacitor arrangement that was used to delivery an earlier cardioversionpulse and that has been recharged before the later cardioversion pulse.In other embodiments, each phase of the biphasic cardioversion pulse maybe delivered from a separate output capacitor arrangement. In otherembodiments, a switching capacitor network may be used to combine outputcapacitor arrangements to deliver the cardioversion pulses of the firststage (400). It will be understood that the initial output voltage,reversal voltage, duration and coupling interval between pulses may bethe same or different for all or for some of the pulses within the rangeof pulse parameters provided for the first stage (400). It will also beunderstood that the pulses shown in FIG. 12 of the first stage (400) mayall be delivered through the same far-field electrode configuration, andin other embodiments the pulses may be delivered as part of a rotatingset of PUFFT pulses delivered through different far-field electrodeconfigurations.

Referring to FIG. 13, an embodiment of the second stage (402) is shown.In this embodiment, each of six monophasic far-field low voltage pulsesare delivered from the same output capacitor arrangement that isrecharged between successive pulses, although the pulses may each bedelivered from separate output capacitor arrangements or from feweroutput capacitor arrangements than the total number of pulses in thesecond stage (402). Alternatively, the pulses may be delivered directlyfrom a charge pump, voltage booster or other similar kind of chargestorage arrangement powered by a battery system. As with the first stage(400), it will be understood that the initial output voltage, durationand coupling interval between pulses of the second stage (402) may bethe same or different for all or for some of the pulses within the rangeof pulse parameters provided for the second stage (402). It will also beunderstood that the pulses shown in FIG. 13 of the second stage (402)may all be delivered through the same far-field electrode configuration,and in other embodiments the pulses may be delivered as part of arotating set of PUFFT pulses delivered through different far-fieldelectrode configurations. The far-field electrode configuration for thesecond stage (402) may be the same as, or different than, the far-fieldelectrode configuration utilized for the first stage (400).

Referring to FIG. 14, an embodiment of the third stage (404) is shown.In this embodiment, each of eight monophasic near-field low voltagepulses are delivered from the same output capacitor arrangement that isrecharged between successive pulses, although the pulses may each bedelivered from separate output capacitor arrangements or from feweroutput capacitor arrangements than the total number of pulses in thethird stage (404). Alternatively, the pulses may be delivered directlyfrom a charge pump, voltage booster or other similar kind of chargestorage arrangement powered by a battery system. In one embodiment, thesame output capacitor arrangement is used to deliver the second stagepulses and the third stage pulses. As with the first stage (400) andsecond stage (402), it will be understood that the initial outputvoltage, duration, and coupling interval between pulses of the thirdstage (404) may be the same or different for all or for some of thepulses within the range of pulse parameters provided for the third stage(404). It will also be understood that the pulses shown in FIG. 14 ofthe third stage (404) may all be delivered through the same near-fieldelectrode configuration, and in other embodiments the pulses may bedelivered as part of a rotating set of PUFFT pulses delivered throughdifferent near-field electrode configurations. In some embodiments, thenear-field electrode configuration may be a monopolar electrodearrangement, and in other embodiments, the near-field electrodeconfiguration may be a bipolar electrode arrangement.

Referring to FIGS. 15 and 16, a multi-therapy embodiment of thethree-stage atrial cardioversion therapy is shown. In this embodiment,the unpinning stage 1 (400) and anti-repinning stage 2 (402) are eachrepeated in sequence as part of the overall atrial cardioversionmulti-therapy before delivery of the extinguishing stage 3 (404). Aswith the embodiment shown in FIG. 11, the parameters for each of thestages, and each of the pulses within each stage, may be the same ordifferent for different stages and/or different pulses within eachstage. Generally, for multi-therapy, termination of the atrialarrhythmia may be confirmed between three-stage therapies, but notbetween individual stages (first, second, or third stages) of athree-stage therapy.

Referring to FIGS. 17 and 18, an alternate embodiment of the three-stageatrial cardioversion therapy is shown. In this embodiment, the unpinningstage 1 (400) and anti-repinning stage 2 (402), as well as theextinguishing stage 3 (404) are each repeated in sequence as part of theoverall atrial cardioversion therapy (28), followed by a repeateddelivery of all three of the stages before completion of the atrialcardioversion therapy (28). As with the embodiment shown in FIG. 11, theparameters for each of the stages, and each of the pulses within eachstage, may be the same or different for different stages and/ordifferent pulses within each stage.

Referring now to FIGS. 19A-19B and 20, a detailed description of theconstruction of an embodiment of the three-stage atrial cardioversionsystem is described. In the example embodiment depicted in FIG. 19A at ahigh level, an atrial arrhythmia treatment apparatus 500 includes aplurality of electrodes 502 adapted to be implanted proximate an atriumof a heart of a patient to deliver far field pulses and a plurality ofelectrodes 504 adapted to implanted proximate the atrium of the heart ofthe patient to deliver near field pulses and sense cardiac signals. Thehousing of apparatus 500 can serve as one of the far-field electrodes502 or near-field electrodes 504. Additionally, far-field electrodes 502and near-field electrodes 504 can share at least one common electrode insome embodiments. An implantable therapy generator 506 is operablyconnected to the electrodes and includes a battery system 508 (or othersuitable on-board energy source such as super capacitors, for example)and one or more power supply circuits 510 operably coupled and providingpower to sensing circuitry 512, detection circuitry 514, controlcircuitry 516 and therapy circuitry 518 of the implantable therapygenerator. In one type of embodiment, therapy circuitry 518 includes aspecialized power supply that is fed directly from battery system 508,bypassing power supply circuitry 510. Sensing circuitry 512 sensescardiac signals representative of atrial activity and ventricularactivity. Detection circuitry 514 evaluates the cardiac signalsrepresentative of atrial activity to determine an atrial cycle lengthand detect an atrial arrhythmia based at least in part on the atrialcycle length. Control circuitry 516, in response to the atrialarrhythmia, controls generation, and selective delivery of a three-stageatrial cardioversion therapy to electrodes 502 and 504, with each stagehaving an inter-stage delay of between 100 and 400 milliseconds and, inan embodiment, without confirmation of conversion of the atrialarrhythmia during the three-stage atrial cardioversion therapy. In otherembodiments, the inter-stage delay may be shortened, such that theinter-stage delay ranges from 50 to 400 milliseconds. In variousembodiments, detection circuitry 514, control circuitry 516 and therapycircuitry 518 can share components. For example, in one embodiment, acommon microcontroller can be a part of detection circuitry 514, controlcircuitry 516 and therapy circuitry 518.

The therapy circuitry 518 is operably connected to electrodes 502 and504 and control circuitry 516. FIG. 19B illustrates an examplearrangement of therapy circuitry 518 according to one type ofembodiment. Therapy circuitry 518 can include its own power supplycircuit 602, which is fed from battery system 508. Power supply circuit602 can be a simple voltage regulator, or it can be a current limitingcircuit that functions to prevent therapy circuitry (which has thegreatest power demands of all the circuitry in the device) from drawingtoo much power and, consequently, causing a drop in the supply voltagebelow a sufficient level to power the controller and other criticalcomponents. Alternatively, power supply circuit 602 can be implementedin power supply circuit 510; or, in one type of embodiment, power supplycircuit 602 can be omitted entirely, such that charging circuit 604 isfed directly from battery system 508.

Charging circuit 604 is a voltage converter circuit that producesvoltages at the levels needed for the stimulation waveform. The input tocharging circuit is a voltage at or near the voltage of battery system508, which in one embodiment is between 3 and 12 volts. Since thestimulation waveform, particularly the first stage, is at a much highervoltage, up to around 100 volts, a boosting topology is used forcharging circuit 604. Any suitable boosting circuit may be employed tothis end, including a switching regulator utilizing one or moreinductive elements (e.g., transformer, inductor, etc.), or a switchingregulator utilizing capacitive elements (e.g., charge pump).

FIGS. 20A-20F illustrate various known topologies for voltage boostingcircuits that can be utilized as part of charging circuit 604 accordingto various embodiments. FIG. 20A illustrates a basic boost convertertopology. The boost converter of FIG. 20A utilizes a single inductorindicated at L1 to store energy in each cycle of switch SW. When switchSW closes, inductor L1 is energized and develops a self-induced magneticfield. When switch SW opens, the voltage at the L1-SW-D1 node is boostedas the magnetic field in inductor L1 collapses. The associated currentpasses through blocking diode D1 and charges energy storage capacitorC_(out) to a voltage greater than input voltage V_(in).

FIG. 20B illustrates a flyback converter topology. The flyback converterutilizes transformer T1 as an energy storage device as well as a step-uptransformer. When switch SW is closed, the primary coil of transformerT1 is energized in similar fashion to inductor L1 of FIG. 20A. Whenswitch SW opens, the voltage across the primary coil is reversed andboosted due to the collapsing magnetic field in the primary. Thechanging voltages of the primary coil are magnetically coupled to thesecondary coil, which typically has a greater number of windings tofurther step-up the voltage on the secondary side. A typical turns ratiofor defibrillator signal applications in certain embodiments is Np:Ns ofabout 1:15, where Np is the number of primary turns and Ns is the numberof secondary turns. The high voltage across the secondary coil isrectified by the diode and stored in capacitor C_(out).

FIG. 20C illustrates a single ended primary inductance converter(“SEPIC”), which offers certain advantages over other power convertertopologies. For instance, the SEPIC converter offers an advantage of notrequiring significant energy storage in the transformer. Since most ofthe energy in a transformer is stored in its gap, this reduces the gaplength requirement for the transformer. Battery voltage is applied atVIN and the switching element is switched at a fixed frequency and aduty cycle that is varied according to feedback of battery current intothe power converter and output voltage. Voltage from the output of thestep up transformer (T1) is rectified by the diode D1 to generate outputvoltage on C_(out).

FIG. 20D illustrates a variation of the SEPIC converter of FIG. 20C. TheSEPIC topology of FIG. 20D has an additional inductive component (L1).The additional inductor L1 can be implemented either discretely, or canbe magnetically coupled with the high voltage transformer into a singlemagnetic structure, as depicted in FIG. 20D.

FIG. 20E illustrates a Cuk converter topology. A Cuk converter comprisestwo inductors, L1 and L2, two capacitors, Cl and C_(out), switch SW, anddiode D1. Capacitor C is used to transfer energy and is connectedalternately to the input and to the output of the converter via thecommutation of the transistor and the diode. The two inductors L1 and L2are used to convert, respectively, the input voltage source (V₁) and theoutput voltage at capacitor C_(out) into current sources. Similarly tothe voltage converter circuits described above, the ratio of outputvoltage to input voltage is related to the duty cycling of switch SW.Optionally, inductors L1 and L2 can be magnetically coupled as indicatedT1*.

FIG. 20F illustrates a basic charge pump topology for multiplying theinput voltage. The example shown is a Cockcroft-Walton multiplyingcircuit. Three capacitors (C_(A), C_(B), and C_(c)), each of capacity C,are connected in series, and capacitor C_(A) is connected to the supplyvoltage, V_(DD). During phase φ, capacitor C₁ is connected to C_(A) andcharged to voltage V_(DD).

When the switches change position during the next cycle, φ_(b),capacitor C₁ will share its charge with capacitor C_(B), and both willbe charged to V_(DD)/2 if they have equal capacity. In the next cycle,C₂ and C_(B) will be connected and share a potential of V_(DD)/4, whileC₁ is once again charged to V_(DD). As this process continues for a fewcycles, charge will be transferred to all the capacitors until apotential of 3V_(DD) is developed across the output Vout. Additionalstages may be added to increase the voltage multiplication.

Referring again to FIG. 19B, pulse energy storage circuit 606 can takevarious forms. Generally, pulse energy storage circuit has energystorage capacity sufficient to store either all three stages of theatrial cardioversion therapy, or a portion of the therapy's energy,provided that the arrangement of energy storage circuit 606 and chargingcircuit 604 supports the ability to recharge portions of the energystorage circuit 606 while other portions thereof are discharging or areabout to discharge during application of the electrotherapy. FIG. 20Gillustrates a basic example of energy storage circuit 606, in whichthere are three separate storage reservoirs for each of the three stagesof the electrotherapy. Storage reservoir 606 a stores the energy for thefirst stage; storage reservoir 606 b for the second; and 606 c for thethird. Each storage reservoir can have one, or a plurality of storageelements. In one type of embodiment, each storage reservoir has aplurality of storage element groups, with each storage element groupindividually switchably selectable for charging and discharging. Thestorage elements can take any suitable form, including capacitors of asuitable technology, e.g., electrolytic, tantalum film, ceramic chip,supercap, or the like.

Storage reservoirs 606 a-606 c are coupled to charging circuit 604 viaselector switch 607. Selector switch 607 can be implemented with aanalog multiplexer, transmission gates, or any other suitable electronicswitching arrangement. Selector switch 607 is controlled by controllercircuit 614 in this example.

Referring again to FIG. 19B, wave shaping circuit 608 regulates theapplication of the electrotherapy by selecting, and controlling thedischarging of the energy stored in energy storage circuit 606. In oneembodiment, wave shaping circuit 608 is in the form of a H-bridgetopology, as illustrated in FIG. 20G. Switches S1-S4 are individuallycontrolled by controller circuit 614. The H-bridge topology facilitatessteering, or reversing the polarity, of the 10 electrotherapy signals,enabling a biphasic shock to be applied from a single-polarity energystorage reservoir. Other forms of switchable coupling are alsocontemplated for other embodiments. For instance, a set of analogtransmission gates can be used, such that each storage reservoir 606a-606 c is individually selectable. In this latter example, separatecapacitors of opposite polarity are used for storing the charge for eachphase of the biphasic unpinning waveform of the first electrotherapyphase.

Referring again to FIG. 19B, electrode coupling circuit 610 operates toselect which of the multiple sets of patient electrodes 612 are coupledto the output of the wave shaping circuit 608. Electrode couplingcircuit 610 can be implemented in one example embodiment using a set ofanalog multiplexers that are controlled by controller circuit 614.

In various other embodiments, the functionality of charging circuit 604and pulse energy storage circuit 606 can be combined into a singlecircuit 620, such as a charge pump arrangement, in which certain ones ofthe capacitors are also used for both, building up charge, and storingthe pulse energy for the electrotherapy. In another variation, the pulseenergy storage circuit 606 can be one and the same circuit, as the waveshaping circuit 608, depicted at 622, such as, for example, wheremultiple different capacitors are used to store each individual pulse,and where the electrode coupling circuit has the capability toindividually select which capacitors are switched in to whichelectrodes. Moreover, in yet another variation, charging circuit 604,pulse energy storage circuit 606, and wave shaping circuit 608 can becombined as a single circuit implementation 624, which can beimplemented as a combination of circuits 620 and 622.

Referring now to FIGS. 21 and 22, exemplary EKG outputs are shown withthe three-stage atrial cardioversion therapy overlayed to demonstratehow the three-stage atrial cardioversion therapy successfully convertsan atrial arrhythmia. FIG. 21 illustrates two curves, the top curveshowing the signal measured with the EKG lead; and the top curve showingthe signal measured with another lead in the atrium. The electrotherapyis applied from the RAA to the RAA. As shown, in the first stage, twounpinning biphasic shocks at 30V with an interval of 40 ms are applied.Then, in the second stage, eight anti-repinning monophasic shocks at 3Vare applied with an interval of 100 ms using the same electrodes asthose in the first stage. Subsequently, in the third stage, eight pacingstimuli are applied with an interval of 100 ms. The third stage isapplied via a RA epicardial pacing electrode. As shown in the lowercurve, the atrial fibrillation is restored to a normal sinus rhythmfollowing administration of the therapy. FIG. 22 depicts a similar pairof curves, except that the three-stage electrotherapy is applied inthree trials. In the first trial, the first stage applied has fiveunpinning biphasic shocks at 20V with an interval of 20 ms. In thesecond stage of the first trial, eight anti-repinning monophasic shocksat 3V with an interval of 100 ms are applied from the same electrodes asthe first stage. In the third stage of the first trial, eight pacingstimuli with an interval of 100 ms are applied from the RA epicardialpacing electrode.

The second and third trials of the three-stage therapy are applied insimilar fashion, except that in the first stage of trials 2 and 3, fiveunpinning biphasic shocks are applied at 30V with an interval of 20 ms.As can be seen in the lower curve of FIG. 22, the atrial EKG indicatesrestoration of a normal sinus rhythm following administration of thethree trials.

Referring now to FIG. 23, experimental results of a comparison of theresults in terms of energy required for successful conversion of AF forthree different electrode configuration vectors is shown for a shockonly protocol, a shock followed by ATP and for the three-stage atrialcardioversion therapy in accordance with an embodiment of the presentinvention.

In the first part of the study, eight mongrel dogs were used. Two diskelectrodes with a diameter of 1″ were placed on the right atria (RAA)and the left atria appendage (LAA), respectively. AF was induced by therapid atrial pacing in the presence of stimulating bilateral vagus nerveat frequency of 4-20 Hz. AF that lasted for >5 min was defined assustained AF. 1 to 4 monophasic (MP, 10 ms) or biphasic (BP, 6-4 ms)shocks were applied from disk electrodes, followed with or w/o ATPapplied from an atrial epicardium-pacing electrode. All shocks aretriggered by the right ventricular R-wave and applied within 80˜100 msto avoid VF induction. In six dogs, a mainly sustained AF was observedwith dominant frequency of 11.0±1.7 Hz using vagal stimulation at12.0±4.4 Hz. For AF (95% cases), DFT of 1 BP was lower than that of IMP(0.73±0.43 vs. 1.68±0.98 J, p=0.008). DFT of 2 BP was lower than that of2 MP (0.37±0.14 vs. 0.93±0.59 J, p=0.01). DFT of 2 BP was lower thanthat of 1 BP (0.37±0.14 vs. 0.73±0.43 J, p=0.04). There are nosignificant difference among DFTs of 2 BP, 3 BP, and 4 BP, while DFT of4 BP is higher than that of 3 BP (0.53±0.41 vs. 0.39±0.36 J, ns). 2 BPfollowed by 6 pulses of ATP lower the DFT significantly than that of 2BP (0.23±0.05 vs. 0.5±0.08 J, p=0.001). Atrial flutter (5% cases, whichhad dominant frequency of 7.7±0.4 Hz) can easily be converted bymultiple shocks at 0.0003±0.0001 J. or ATP alone.

In the second part of the study, eight mongrel dogs were used. Threedisk electrodes with a diameter of 0.5″ were placed on the RAA, LAA, andsuperior vena cava (SVC). A 3F lead with two 1″ coils was inserted intocoronary sinus. The distal coil is named as coronary sinus distal (CSd)and the proximal coil is named as coronary sinus proximal (CSp). Wetested DFT of shocks applied from three vectors: SVC to CSd, LAA to CSp,and LAA to RAA. Three different combinations of the three stages weretested randomly: 1^(st) stage only, 1^(st) stage followed by 2^(nd)stage, and three stages together, named as therapy 1, therapy 2, andtherapy 3, respectively. In six out of eight dogs, sustained AF withdominant frequency of 9.77±0.88 Hz was induced. In all three vectors,the therapy 3 had the lowest DFT among three therapies. The therapy 1had the highest DFT among three therapies. In vector SVC to CSd, DFTs oftherapy 1, therapy 2, and therapy 3 were 0.53±0.14 vs. 0.35±0.26 vs.0.12±0.070 J. In vector LAA to CSp, DFTs of therapy 1, therapy 2, andtherapy 3 were 0.52±0.14 vs. 0.27±0.27 vs. 0.12±0.074 J. In vector RAAto LAA, DFTs of therapy 1, therapy 2, and therapy 3 were 0.37±0.13 vs.0.27±0.26 vs. 0.097±0.070 J. There is not significant difference amongDFTs of three vectors.

Additional details of the above-described study may be found in thepublished article to Li et al., Low Energy Multi-Stage AtrialDefibrillation Therapy Terminates Atrial Fibrillation with Less Energythan a Single Shock, Circulation Arrhythmia and Electrophysiology,published online Oct. 6, 2011, which is hereby incorporated by referencein its entirety.

Referring now to FIG. 24, an embodiment of the three-stage therapy ofFIG. 11 that was experimentally shown to successfullydefibrillate/cardiovert AF at low energy is depicted. As will bedescribed further below with respect to FIGS. 29 and 30, this particularthree-stage therapy was applied using an implantable device in a chroniccanine model of persistent AF.

In this tested embodiment, first stage (ST1) consisted of two low-energybi-phasic pulses having peak voltages ranging from 10 volts to 100volts. Pulse duration ranged from 4-10 ms, with a pulse-couplinginterval (PCII) ranging from 30 to 50% of the AF CL. The pulses weresynchronized to the R wave and delivered within the ventriculareffective refractory period to avoid inducing ventricular fibrillation.

After delivering first stage (ST1) pulses, an inter-stage delay (II) of50 ms to 400 ms was implemented. More particularly, the interstage delay(II) was 50 ms, followed by second stage (ST2).

Second stage (ST2) consisted of six ultra-low-energy monophasic pulses.Peak voltages ranged from 1 volt to 3 volts, each having an approximatepulse duration of 10 ms. Pulses were delivered at 70% to 100% of the AFCL (pulse-coupling interval PC12). In at least one case, pulses weredelivered at 88% of the AF CL. In this stage, the multiple pulsesdelivered enough energy to capture the atrium, but not the ventricle.Operating in this voltage window above the atrial capture threshold, butbelow the ventricular capture threshold is necessary because the secondstage (ST2) pulses are delivered at 70% to 100% of the AF CL, and notsynchronized to the R wave. If second stage (ST2) voltage or energybecomes too high, there exists a risk of capturing the ventricle andinducing ventricular fibrillation.

After delivering second stage (ST2) pulses, an inter-stage delay of 50ms to 400 ms was implemented. More particularly, the inter-stage delaywas 50 ms, followed by third stage (ST3).

Third stage (ST3) consisted of pacing the atrium generally at 70% to100% of the AF CL (PC13 of 70% to 100% of AFCL), but more particularlyat 88% of the AF CL, at three times the atrial capture threshold.

Referring also to FIGS. 25A-25D, a chronic canine model of persistent AFthrough chronic high-rate atrial pacing was created to implement thethree-stage therapy of FIG. 24.

In this study, a transvenous endocardial lead system was implanted todeliver the sequential, three-stage therapy of FIG. 24 in a closed-chestcanine model of persistent AF induced by rapid atrial pacing. Bipolarpace/shock leads were implanted in the right atrium (RA) and leftpulmonary artery (LPA), reproducing an RA to distal coronary sinusvector. Persistent AF was induced by high-rate atrial pacing for 8-12weeks. The atrial DFTs of three-stage therapy and a single biphasicshock were delivered through the RA-LPA vector and measured.

The three-stage therapy, as depicted and described above with respect toFIG. 24, consisted of three sequential stages: two biphasic shocks(pulses) delivered within one AF cycle length as well as ventriculareffective refractory period; six monophasic pulses, each delivered withan interval of 88% of the AF CL at 50% of the ventricular capturevoltage; and anti-tachycardia pacing (ATP; 8 pulses with an interval 88%of the AF CL) delivered through the RA bipole.

Referring specifically to FIGS. 25A-25D, lead placement of the caninemodel is depicted. Bipolar pacing/sensing lead 500 was implanted in theright atrial appendage (RAA) and SVC as depicted. Lead 502 withelectrode 504 was implanted in the CS as depicted. Lead 506 withproximal and distal electrodes 508 a and 508 b was implanted in the LP Aas depicted. An LPA lead was chosen due to the anatomical differencesbetween the canine and human coronary sinus. The CS of a dog tapersquickly, preventing insertion of leads into the lateral CS, so anLPA-implanted lead was used to approximate the lateral CS of a human.

Atrial tachypacing pulses were delivered from an implantable device,including a Medtronic Entrust implantable cardioverter defibrillatormanufactured by Medtronic of Minneapolis, Minn.

The above-described implantable, closed-chest model was selectedrecognizing that previous work was done in an acute vagus nervestimulated AF canine model, which is much different than humans with AF.Secondly, previous studies often used defibrillation disks in anopen-chest model, which is generally not a realistic approach forhumans.

Results indicated a mean dominant frequency of AF of 114±17 ms. Theimpedance of the RA-LPA vector was 103.1±15.7 Ohms. As depicted,three-stage therapy significantly decreased the atrial DFT compared to asingle biphasic shock with respect to total energy (0.27±0.14 J versus1.45±0.36 J; p<0.001) and peak voltage (42.3±14.8 V versus 161.2±18.7 V,p<0.001).

During the study, fourteen dogs were implanted; AF was induced in ten ofthe dogs, with an average time between implantation and AF inductionbeing six weeks+/−two weeks. Twenty-two defibrillation studies wereperformed in six dogs, and 127 terminations of AF completed with theaverage AF CL and mean impedance described above.

Referring to FIGS. 26-27, sample atrial DFTs resulting from thethree-stage therapy of the claimed invention were significantly lowerthan those of a conventional biphasic shock therapy.

Referring specifically to FIG. 26, a bar chart depicts an overallvoltage and energy comparison of atrial DFTs of a single biphasic shockand the three-stage therapy of the claimed invention. Also depicted arethe corresponding sample ECGs.

Bar 510 depicts the voltage and energy characteristics of an atrial DFTcorresponding to a single, biphasic shock. ECG 512 depicts the ECG ofthe atrial arrhythmia interrupted by the biphasic shock as indicated bythe arrow. As depicted, the DFT voltage was 170.0 volts at a totalenergy of 1.649 Joules.

Bar 514 depicts the voltage and energy characteristics of an atrial DFTcorresponding to the three-stage therapy of the claimed invention asdescribed above. ECG 516 depicts the ECG of the atrial arrhythmiainterrupted by the three-stage therapy at a timing indicated by thearrow. As depicted, the DFT voltage was 2.5 volts at a total energy of0.016 Joules.

As such, the AF was terminated by the three-stage therapy withsignificantly less energy and lower peak voltage as compared to thesingle biphasic shock.

Referring to FIG. 27, in another example, AF was terminated with lessenergy and lower peak voltage using the three-stage therapy of theclaimed invention as compared to a single biphasic shock.

Peak voltage was reduced to 42.3±14.8 V versus 161.2±18.7 V for a singleBP shock (p<0.001).

Atrial DFT was reduced to 0.27±0.14 J versus 1.45±0.36 J for a single BPshock (p<0.001).

Consequently, the three-stage electrotherapy of the present inventionterminates persistent AF with significantly lower peak voltage anddramatically lower total energy compared to a conventional singlebiphasic shock. Further, this therapy may enable device based painlessatrial defibrillation by defibrillating at thresholds below the humanpain threshold.

The embodiments above are intended to be illustrative and not limiting.Additional embodiments are within the claims. In addition, althoughaspects of the present invention have been described with reference toparticular embodiments, those skilled in the art will recognize thatchanges can be made in form and detail without departing from the spiritand scope of the invention, as defined by the claims.

Persons of ordinary skill in the relevant arts will recognize that theinvention may comprise fewer features than illustrated in any individualembodiment described above. The embodiments described herein are notmeant to be an exhaustive presentation of the ways in which the variousfeatures of the invention may be combined. Accordingly, the embodimentsare not mutually exclusive combinations of features; rather, theinvention may comprise a combination of different individual featuresselected from different individual embodiments, as understood by personsof ordinary skill in the art.

Any incorporation by reference of documents above is limited such thatno subject matter is incorporated that is contrary to the explicitdisclosure herein. Any incorporation by reference of documents above isfurther limited such that no claims included in the documents areincorporated by reference herein. Any incorporation by reference ofdocuments above is yet further limited such that any definitionsprovided in the documents are not incorporated by reference hereinunless expressly included herein.

For purposes of interpreting the claims for the present invention, it isexpressly intended that the provisions of Section 112, sixth paragraphof 35 U.S.C. are not to be invoked unless the specific terms “means for”or “step for” are recited in a claim.

The invention claimed is:
 1. An implantable therapy generator,comprising: detection circuitry configured to evaluate one or moresensed cardiac signals representative of atrial activity and detect anatrial arrhythmia; control circuitry operably connected to the detectioncircuitry that, in response to the atrial arrhythmia, controlsgeneration and selective delivery of a therapy without confirmation ofconversion of the atrial arrhythmia during the therapy, the therapyincluding: a first stage set of electrical pulses delivered via a firstimplantable electrode within a ventricular refractory period todestabilize a reentry associated with the atrial arrhythmia; and asecond stage set of electrical pulses delivered via at least two of thefirst implantable electrode and a second implantable electrode, thesecond stage set of electrical pulses to terminate the reentry; whereinthe first stage and the second stage are separated by a delay having aduration between 50 to 400 milliseconds, wherein the first implantableelectrode comprises a far field electrode, and wherein the secondimplantable electrode comprises a near field electrode, wherein the farfield electrode is a portion of an exterior surface of a housing of theimplantable therapy generator.
 2. The implantable therapy generator ofclaim 1, wherein the second stage is delivered via at least two of thefirst implantable electrode and at least one of the second implantableelectrodes.
 3. The implantable therapy generator of claim 1, wherein thetherapy comprises an atrial cardioversion therapy.
 4. The implantabletherapy generator of claim 1, wherein the first stage has a totalduration of less than one atrial cycle length and includes at least twoand less than ten electrical pulses of at least 10 volts and not morethan 100 volts, the atrial cycle length determined by the detectioncircuitry based on the one or more sensed cardiac signals; and thesecond stage includes at least five and less than ten pulses of lessthan 50% of a ventricular far-field excitation threshold with a pulsecoupling interval between electrical pulses of between 70-100% of theatrial cycle length.
 5. The implantable therapy generator of claim 1,wherein the therapy is delivered in a sequence of one of the first stageand one of the second stage.
 6. The implantable therapy generator ofclaim 1, wherein the first stage and the second stage are delivered inaccordance with a set of therapy parameters for the electrical pulses ofeach stage that are programmed in response to feedback of a patient inwhom the apparatus is implanted so as to provide an effective treatmentof the atrial arrhythmia for the patient at a pain sensation that istolerable to the patient.
 7. The implantable therapy generator of claim1, further comprising a heuristic learning algorithm configured todynamically modify a set of therapy parameters for the electrical pulsesof each stage in response to an effectiveness of the therapy.
 8. Theimplantable therapy generator of claim 1, wherein the first stageconsists of two electrical pulses.
 9. The implantable therapy generatorof claim 1, wherein the first stage set of electrical pulses comprisesbiphasic pulses.
 10. An implantable therapy generator, comprising:detection circuitry configured to evaluate one or more sensed cardiacsignals representative of atrial activity and detect an atrialarrhythmia; and control circuitry operably connected to the detectioncircuitry that, in response to the atrial arrhythmia, controlsgeneration and delivery of a therapy without confirmation of conversionof the atrial arrhythmia during the therapy, the therapy including: afirst stage set of electrical pulses delivered via a first implantableelectrode within a ventricular refractory period to unpin one or moresingularities associated with the atrial arrhythmia; a second stage setof electrical pulses delivered via the first implantable electrode toinhibit repinning of the one or more singularities; and a third stageset of electrical pulses delivered via a second implantable electrode toextinguish the one or more singularities; wherein each stage isseparated by an inter-stage delay and wherein at least one of theinter-stage delays has a duration of between 50 to 400 milliseconds. 11.The implantable therapy generator of claim 10, wherein the firstimplantable electrode comprises a far field electrode, and wherein thesecond implantable electrode comprises a near field electrode.
 12. Theimplantable therapy generator of claim 11, wherein the far fieldelectrode is a portion of an exterior surface of a housing of theimplantable therapy generator.
 13. The implantable therapy generator ofclaim 10, wherein the second stage is delivered via at least two of thefirst implantable electrode and at least one of the second implantableelectrodes.
 14. The implantable therapy generator of claim 10, whereinthe therapy comprises an atrial cardioversion therapy.
 15. Theimplantable therapy generator of claim 10, wherein the first stage has atotal duration of less than one atrial cycle length and includes atleast two and less than ten electrical pulses of at least 10 volts andnot more than 100 volts, the atrial cycle length determined by thedetection circuitry based on the one or more sensed cardiac signals; thesecond stage includes at least five and less than ten electrical pulsesof less than 50% of a ventricular far-field excitation threshold with apulse coupling interval between pulses of between 70-100% of the atrialcycle length; and the third stage includes at least five and less thanten near field pulses at a voltage of up to three times an atrialcapture threshold with a pulse duration of more than 0.2 and less than 5milliseconds and a pulse coupling interval of between 70-100% of theatrial cycle length.
 16. The implantable therapy generator of claim 10,wherein the therapy is delivered in a sequence of one of the firststage, one of the second stage and one of the third stage.
 17. Theimplantable therapy generator of claim 10, wherein the therapy isdelivered in sequence of one of the first stage, one of the secondstage, one of the first stage, one of the second stage and one of thethird stage.
 18. The implantable therapy generator of claim 10, whereinthe therapy is delivered in accordance with a set of therapy parametersfor the electrical pulses of each stage that are programmed in responseto feedback of a patient in whom the apparatus is implanted so as toprovide an effective treatment of the atrial arrhythmia for the patientat a pain sensation that is tolerable to the patient.
 19. Theimplantable therapy generator of claim 10, further comprising aheuristic learning algorithm configured to dynamically modify a set oftherapy parameters for the pulses of each stage in response to aneffectiveness of the therapy.
 20. The implantable therapy generator ofclaim 10, wherein the first stage consists of two electrical pulses. 21.The implantable therapy generator of claim 10, wherein the first stagehas a total duration of 30% to 50% of one cycle length of the atrialarrhythmia, the cycle length determined by the detection circuitry basedon the one or more sensed cardiac signals.
 22. The implantable therapygenerator of claim 10, wherein the first stage electrical pulsescomprise biphasic pulses.
 23. A method, comprising: providing animplantable therapy generator configured for coupling to a plurality ofimplantable electrodes; and providing instructions recorded on at leastone tangible medium and including: implanting the therapy generator andthe plurality of electrodes within a patient; and causing the implantedtherapy generator to deliver a three-stage atrial arrhythmia therapywhich includes a first stage delivered to the at least one far fieldelectrode for unpinning of one or more singularities associated with anatrial arrhythmia, a second stage delivered to the at least one farfield electrode for anti-repinning of the one or more singularitiesassociated with the atrial arrhythmia, and a third stage delivered tothe at least one near field electrodes for extinguishing of the one ormore singularities associated with the atrial arrhythmia, wherein eachstage is separated by an inter-stage delay and wherein at least one ofthe inter-stage delays has a duration of between 50 to 400 milliseconds.24. The method of claim 23, wherein the instructions for implanting thetherapy generator and the plurality of electrodes further includeimplanting at least one far field electrode and at least one near fieldelectrode proximate an atrium of a heart of the patient.
 25. Animplantable therapy generator, comprising: detection circuitryconfigured to evaluate one or more sensed cardiac signals representativeof atrial activity and detect an atrial arrhythmia; control circuitryoperably connected to the detection circuitry that, in response to theatrial arrhythmia, controls generation and selective delivery of atherapy without confirmation of conversion of the atrial arrhythmiaduring the therapy, the therapy including: a first stage set ofelectrical pulses delivered via a first implantable electrode within aventricular refractory period to destabilize a reentry associated withthe atrial arrhythmia; and a second stage set of electrical pulsesdelivered via at least two of the first implantable electrode and asecond implantable electrode, the second stage set of electrical pulsesto terminate the reentry; wherein the first stage and the second stageare separated by a delay having a duration between 50 to 400milliseconds wherein the first stage has a total duration of 30% to 50%of one cycle length of the atrial arrhythmia, the cycle lengthdetermined by the detection circuitry based on the one or more sensedcardiac signals.